This is a proposal for the continuation of studies of the molecular basis of somatic hypermutation (SHM) of immunoglobulin (Ig) genes. The discovery of the cytidine deaminase, AID, has clearly identified the deamination of C as the first step in SHM. Based on the current knowledge, the mutation process can be viewed as follows: AID specifically associates with Ig genes (and a few other genes, such as BCL6, IgD, and IgD. AID creates C to U deaminations in both the top and bottom strand of the targeted gene, starting within 200 bp from the promoter and extending for about 1 to 2 kb. The 3' end of the gene is spared. The uracil is repaired in an error-prone fashion, resulting in an excess of transitions over transversions from all four nucleotides. The details of the process are not understood. They can be considered as three major complexes of questions. 1) How are Ig genes (and a few other genes) specifically targeted by AID and how are the mutations restricted to the first 1-2 kb from the promoter? 2) Since AID in vitro is highly restricted to C-deamination in single-stranded, not double-stranded DMA, how can both strands be equally targeted during SHM? 3) How does error-prone repair become involved in the process and how are mutations from A and T created? It is proposed in this grant application to study these questions. The planned experiments are important for determining how the varied repertoire of Ig genes is created with the potential to react against any foreign antigenic substance, including tumor cell antigens. Somatic hypermutation has also been implicated in autoimmune diseases. Furthermore, many B cell lymphomas arise apparently as a consequence of the somatic mutation process. It is likely that understanding the components involved in somatic mutation will aid in understanding the genetic and environmental causes of autoimmunity, and the treatment of infectious diseases and tumors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047380-07
Application #
7233255
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Nasseri, M Faraz
Project Start
2000-05-01
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
7
Fiscal Year
2007
Total Cost
$367,634
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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